This proposal seeks to create new therapies for cancer based on protein nanoparticles encapsidating various therapeutic agents that are connected to the carrier by novel thiol-cleavable linkers. The final goal of this multidisciplinary project is the preparation of targeted bacteriophage Q-beta particles encapsidating a cytotoxic drug connected to its inner surface. The outer surface will display tumor-specific ligands known to specifically target tumor cells. In a proof-of-concept study, a highly active but poorly soluble camptothecin derivative known as SN-38 will be employed. In Aim 1, I will demonstrate that SN-38 can be solubilized by conjugation with thiol- responsive electrophilic 7-oxanorbornadienes (OND). Once taken up by a cell, reaction with cellular glutathione will release the drug to the cytosol in its active form. In Aim 2, I will demonstrate that active targeting of cytotoxic modalites is possible by their encapsidation inside hollow protein nanoparticles displaying tumor- specific ligands. Facile and modular synthesis of OND linkers enables extension of this approach for any drugs, photosensitizers, nucleic acids, and other therapeutic agents. Successful realization of these aims will result in creation of unique therapies that greatly enhance the potential of antineoplastic drugs. PUBLIC HEALTH RELEVANCE: It is commonly recognized that modern anticancer drugs must be targeted, i.e. designed to act specifically on the diseased tissues. The proposed research is aimed at expanding the available arsenal of drug delivery and release systems by investigating novel cleavable linkers that connect a cytotoxic drug SN-38 to tumor-targeted nanoparticles. Ultimately, the incorporation of these state- of-the art cancer therapies into clinical practice is sought.